The strategic goal of this revised application is to develop mechanism-based experimental therapeutic targeting strategies aimed at circumventing 'evasive resistance' to anti-angiogenic therapy, a phenomenon discovered in the course of the current term of this project, whereby tumors whose angiogenic vasculature is disrupted by inhibitors of VEGF signaling acquire means to relapse and recommence growth after a transitory period of beneficial therapeutic response. The general approach involves using mouse models of cancer, principally neuroendocrine pancreatic tumors and glioblastoma, whose histopathology and angiogenic phenotypes mirror human tumors, along with pharmacological agents (monoclonal antibodies, hybrid antibody-ligand traps, and small molecules) targeting regulatory circuits governing tumor angiogenesis and vascular homeostasis. The specific aims of this renewal intend to characterize and identify therapeutic targets for three distinctive mechanisms of evasive resistance to inhibitors of VEGF signaling: Aim 1. Investigate the induction of additional and alternative pro-angiogenic signaling circuits as an evasion mechanism to anti-VEGFR therapy; Aim 2. Evaluate the capability of recruited bone marrow-derived cells (BMD-C) to help circumvent anti-angiogenesis drugs. Aim 3. Elucidate the parameters and assess mechanism-based therapeutic targeting of increased tumor invasiveness in response to angiogenesis inhibition. While much heralded, the arrival of angiogenesis inhibitors into the clinic, in particular ones targeting the VEGF signaling pathway, is not in general resulting in enduring responses, but rather transitory periods of improved quality of life (tumor shrinkage or stabilization; months of survival advantage) followed by renewed tumor growth and progression. The postulates forthcoming from this project to be pursued in its renewal are that 1) a component to such relapse is the induction of evasive resistance to VEGF inhibition, and 2) therapeutic strategies targeting evasive resistance mechanisms hold promise to produce more enduring anti-angiogenic therapies for human cancers. PUBLIC HEALTH RELEVANCE: While much heralded, the arrival of angiogenesis inhibitors into the clinic, in particular ones targeting the VEGF signaling pathway, is not in general resulting in enduring responses, but rather transitory periods of improved quality of life (modest tumor shrinkage or stabilization; months of survival advantage) followed by renewed tumor growth and progression. This project has discovered a basis for such transitory efficacy, involving the induction of three 'evasive resistance' mechanisms: revascularization mediated by alternative angiogenic signals, recruitment of vascular progenitor cells from the bone marrow, and increased invasiveness, parameters to be elucidated in this resubmitted competitive renewal application. Targeting such resistance mechanisms holds promise to produce more enduring anti-angiogenic therapies for human cancers.